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`Third Edition
`L.G. Wade, Jr.
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`SAWAI EX. 1019
`Page 1 of 6
`
`

`

`hird Edition
`
`Organic
`Chemistry
`
`L. G. Wade, Jr.
`
`Whitman College
`
`Prentice Hall
`Upper Saddle River, Nerv Jersey 07458
`
`SAWAI EX. 1019
`Page 2 of 6
`
`

`

`Ill
`
`Library of Congress Cataloging-in-Publication Data
`
`Wade, L. G.
`Organic chemistry/L. G. Wade, Jr.—3rd ed.
`cm.
`P-
`Includes index.
`ISBN 0-13-301631-5
`1. Chemistry, Organic. I. Title.
`QD251.2.W33 1995
`547—-dc20
`
`94-24693
`CIP
`
`Editorial/production supervision: Barbara Marttine Cappuccio
`Acquisitions editor: Deirdre Cavanaugh
`Interior design and page layout: Lorraine Mullaney
`Cover design: Tessie Lou .
`Manufacturing buyer: Lori Bulwin/Alan Fischer
`Managing editor: Kathleen Schiaparelli
`Director of production and manufacturing: David W. Riccardi
`Copy editor: Barbara Ligouri
`Supplements editor: Mary Hornby
`Editorial assistant: Veronica Wade
`
`© 1995,1991,1987 by Prentice Hall, Inc.
`A Simon & Schuster Company
`Upper Saddle River, New Jersey 07458
`All rights reserved. No part of this book may be reproduced, in any form or by any means, without
`permission in writing from the publisher.
`
`COVER ART: BioGrafx .
`A computer-generated representation of a tripeptide, glycylcysteylalanine. In this representation, carbon is
`green, hydrogen is white, nitrogen is blue, oxygen is red, and sulfur is yellow.
`
`Printed in the United States of America
`
`10 9876543
`
`ISBN 0-13-D301b31-S
`
`Prentice-Hall International (UK) Limited, London
`Prentice-Hall of Australia Pty. Limited, Sydney
`Prentice-Hall Canada, Inc., Toronto
`Prentice-Hall Hispanoamericana, S.A., Mexico
`Prentice-Hall of India Private Limited, New Delhi
`Prentice-Hall of Japan, Inc., Tokyo
`Simon & Schuster Asia Pte. Ltd., Singapore
`Editora Prentice-Hall do Brasil, Ltda., Rio de Janeiro
`
`SAWAI EX. 1019
`Page 3 of 6
`
`

`

`I'r-
`
`■Q
`R-q
`
`'t
`
`I f
`
`%
`
`4
`
`f
`
`t1
`
`s
`
`I
`
`Reactions that convert carboxylic acids directly to these derivatives are
`cov-
`ered in this chapter. Reactions that interconvert these and other acid derivatives
`are
`discussed in Chapter 21, Carboxylic Acid Derivatives.^
`
`20-10
`Synthesis and Use
`of Acid Chlorides
`
`Halide ions are excellent leaving groups for nucleophilic acyl substitution; there­
`fore, acyl halides are particularly useful intermediates for making acid derivatives.
`In particular, acid chlorides (acyl chlorides) are easily made and are commonly used
`as an activated form of a carboxylic acid. Both the carbonyl oxygen and the chlorine
`atom withdraw electron density from the acyl carbon atom, making it strongly
`electrophilic. Acid chlorides react with a wide range of nucleophiles, generally
`through the addition-elimination mechanism of nucleophilic acyl substitution.
`
`O
`
`R
`
`Cl
`
`an acid chloride (acyl chloride)
`
`■«)
`
`Cl
`
`±
`
`R—5
`
`Nuc:
`acid chloride
`
`:0:|K
`R—C
`Nuc
`tetrahedral intermediate
`
`Cl
`
`O'
`R—C—Nuc + CD
`
`-)■
`
`acid derivative
`
`n
`
`■i
`
`g
`
`The best reagents for converting carboxylic acids to acid chlorides are thionyl
`chloride (SOClj) and oxalyl chloride (COCl)2, because they form gaseous byprod­
`ucts that do not contaminate the product. Oxalyl chloride is particularly easy to use
`because it boils at 62°C and is easily evaporated from the reaction mixture,
`o
`O
`Cl—S—Cl
`R—C—OH
`o o
`or Cl—C—C—Cl
`
`O
`R—C—Cl
`
`■>
`
`..ij
`
`Examples
`O
`
`(CHj),—C—OH
`
`CH3(CH2),-.^
`
`H
`
`c=c
`
`H
`oleic acid
`
`o
`Cl—s—Cl
`thionyl chloride
`
`CH.icn,),
`H
`
`O
`(CH^l^-C-Cl
`
`:c=c
`
`H
`oleoyl chloride
`(95%)
`
`+ SOjt + HClf
`
`o
`2—CH^—C—OH
`
`o o
`Cl—C—C—Cl
`oxalyl chloride
`
`O
`CHj—c—Cl + HClt + cot + COjt
`
`3-phenylpropanoic acid
`
`3-phenylpropanoyl chloride
`(95%)
`
`Acid chlorides react with alcohols to give esters through a nucleophilic ac^j
`substitution by the addition-elimination mechanism discussed above. Attack y ,
`
`960
`
`Chapter 20 Carboxylic Acids
`
`‘■Kl
`
`■
`
`i
`
`N
`
`’§} Sv
`
`f
`
`SAWAI EX. 1019
`Page 4 of 6
`
`

`

`5 cov­
`es are
`
`I.
`
`'U-
`
`there-
`dives.
`Yused
`lorine
`■ongly m
`erally
`m.
`
`CL
`
`lionyl
`'prod-
`to use
`
`HClf
`
`.r
`
`'it
`
`.4
`
`C02t
`
`!
`
`c acyl
`•ckby ^ M
`
`the alcohol at the electrophilic carbonyl group gives a tetrahedral intermediate. Loss
`of chloride and deprotonation give the ester.
`
`+ R'—OH
`
`R—C^Cl
`R'—O—H
`
`lo'
`^ R—C
`''o2-h
`R'" •
`
`+ Cl-
`
`O'
`
`^ R—C—O—R' + HCl
`ester
`
`This reaction provides an efficient two-step method for converting a carbox­
`ylic acid to an ester. The acid is converted to the acid chloride, which reacts with an
`alcohol to give the ester.
`
`O
`
`R—C—OH
`acid
`
`(COCl)^
`or SOCI2
`
`O
`
`R—C—Cl
`acid chloride
`
`R'—O—H
`alcohol
`
`o
`R—C—O—R' -f HCl
`ester
`
`Example
`
`O
`
`Ph—C—OH
`benzoic acid
`
`soci^
`
`O
`
`CH3CH2—OH
`ethanol
`
`o
`Ph—C—Cl
`Ph—C—O—CH2CH3 + HCl
`benzoyl chloride
`ethyl benzoate
`Ammonia and amines react with acid chlorides to give amides, also through
`the addition-elimination mechanism of nucleophilic acyl substitution. A carbox­
`ylic acid is efficiently converted to an amide by forming the acid chloride, which
`reacts with an amine to give the amide.
`O
`
`O
`
`R—C—Cl + R'—NH2
`acid chloride
`amine
`
`R—C—NH—R' + HCl
`amide
`
`Example
`
`O
`
`CH3—C—Cl -b CH3—NH2
`acetyl chloride
`methylamine
`
`O H
`CH3—c—N—CH3 + HCl
`iV-methylacetamide
`
`PROBLEM 20-12
`Give mechanisms for the nucleophilic acyl substitutions to form ethyl benzoate and
`A-methylacetamide as shown above.
`
`PROBLEM 20-13
`Show how you would use an acid chloride as an intermediate to synthesize
`(a) Al-phenylbenzamdde (PhCONHPh) from benzoic acid and aniline.
`(b) Phenyl propionate (CH3CH2COOPh) from propionic acid and phenol.
`
`20-10 Synthesis and Use of Acid Chlorides
`
`961
`
`SAWAI EX. 1019
`Page 5 of 6
`
`

`

`‘Oi
`
`7
`R—C—Cl + HO—C—R'
`
`O
`
`Conversion of an acid chloride to an anhydride
`■o-f1^
`a
`R—C-^Cl
`
`acid chloride
`
`acid
`
`H C
`
`nucleophilic attack
`
`tetrahedral intermediate
`
`Example
`
`o
`o
`CHjCCHjIs—c—Cl + CH3(CH2)5—c—OH
`heptanoyl chloride
`heptanoic acid
`
`Y
`
`R—C
`
`O'
`
`?
`
`R—C—O—C—R'
`anhydride
`+ H—Cl
`
`o
`o
`CHslCHjls—C—O—C—(CH2)5CH3
`heptanoic anhydride
`
`R'
`
`zation
`abili-
`5 less
`
`r
`
`R
`
`ive.
`ictive
`to an
`Tiide.
`to the
`iima-
`toits
`
`y the
`) less
`
`■'
`
`1
`
`■vv.
`
`iffli
`
`t
`
`O
`
`O
`
`CH3—(CH2)4—c—Cl +
`
`NH2
`
`■»
`
`CH3—(CH2)4—c—NH
`
`+ HCl
`
`hexanoyl chloride
`
`cyclohexylamine
`
`Al-cyclohexylhexanamide
`
`21-5 Interconversion of Add Derivatives by Nucleophilic Acyl Substitution
`
`999
`
`Conversion of an acid chloride to an ester
`
`O’
`
`7
`R—C—Cl + R'—OH
`acid chloride
`alcohol
`
`nucleophilic attack
`
`R—C—Cl
`
`R
`H
`tetrahedral intermediate
`
`O’
`
`> R—C
`:O^H<
`
`+ Cl^
`
`R
`
`’O’
`
`/
`
`R—C—O—R
`ester
`+ HCl
`
`Example
`
`cyclopentanecarbonyl
`chloride
`
`OH
`
`CH—CH3
`
`2-propanol
`
`0CH(CH3)2 + HCl
`
`2-propyl
`cyclopentanecarboxylate
`
`Conversion of an acid chloride to an amide
`
`'O'
`
`R—c—g: / R'N—H <=^ R—Ct-cu -
`acid chloride
`amine
`nucleophilic attack
`
`V..
`
`R—C
`
`:o'
`\+
`R'N^H
`
`•■cu
`
`» R—C
`
`:o'
`•NR2
`+ HCl
`
`R^N—H
`tetrahedral intermediate
`Reaction of an acid chloride with ammonia gives a primary amide; with a primary
`amine this reaction gives a secondary amide; and with a secondary amine it gives a
`tertiary amide.
`
`SAWAI EX. 1019
`Page 6 of 6
`
`